1. Field of the Invention
This invention relates to the selective amidination of diamines, and especially to .omega.-guanidino-.alpha.-amino acids, and to the preparation of these acids, their functional derivatives, and compounds, such as peptides, containing them.
2. Background to the Invention
Published European Patent Application No. 196,841 describes a number of N.sup.G,N.sup.G' -dialkylguanidino dipeptides, which are stated to be useful as angiotensin-converting enzyme (ACE) inhibitors. These dipeptides may be considered to contain the modified amino acids N.sup.G,N.sup.G' -dialkylarginine, N.sup.G,N.sup.G' -dialkylhomoarginine, and N.sup.G,N.sup.G' -dialkyldihomoarginine; and may be prepared by a number of methods, which include (1) the reductive condensation of one of these amino acids with an .alpha.-ketoamide to form the dipeptide, and (2) the alkylation of a precursor dipeptide containing an .omega.-amine group, e.g. a dipeptide based on ornithine, lysine, or homolysine, with an alkylating formamidine derivative (an amidinating agent). Both of these synthetic methods involve the amidination of an .omega.-amine group with an alkylating formamidine derivative such as a haloformamidine or an (alkylthio)formamidine (an S-alkylisothiourea): in (1) in the preparation of a starting material, and in (2) in the reaction itself, and are discussed in the above-mentioned application, as are the syntheses of the starting materials.
A synthesis of ethyl N.sup.G,N.sup.G' -diethyl-L-homoarginate hydrochloride is disclosed in J. J. Nestor, Jr., et al., "Peptides--Structure and Function", Proc. Eighth Amer. Peptide Symposium, V. J. Hruby and D. H. Rich, Eds., Pierce Chem. Co., Rockford Ill., 1984, pp. 861-4. However, the use of an S-alkylisothiourea as an alkylating agent is attended with two disadvantages: first, the yield of the desired .omega.-guanidino acid is low; and second, the byproduct of the reaction is a noxious alkyl mercaptan. If an S-methylisothiourea is chosen, as is commonly done, methyl mercaptan (a gas detectable at a concentration of 1 ppb), results.
W. Walter, Angew. Chem., 67, 1955, p. 275, describes the reaction of formamidinesulfinic acid with glycine under basic conditions to yield 36% of N-(aminoiminomethyl)glycine, an .alpha.-guanidino acid. British Patent No. 1,587,258 (Aktieselskabet Gea) describes the preparation of guanidines by the reaction of ammmonia and primary amines with formamidinesulfonic acids, which may be mono- or di-substituted with alkyl or phenylalkyl groups. C. A. Maryanoff et al., J. Org. Chem., 51, 1986, pp. 1882-4, describe the reaction of mono(alkyl or aryl)formamidinesulfonic acids with primary and secondary amines to prepare guanidines. U.S. Pat. No. 4,656,270 (Maryanoff et al.) describes a process for the preparation of certain guanidines, which process includes the preparation of an N-arylformamidinesulfonic acid by the oxidation of the corresponding N-arylthiourea with hydrogen peroxide in the presence of a molybdenum catalyst. U.S. Pat. No. 4,656,291 (Maryanoff et al.) describes a process for the preparation of certain guanidines, which process includes the preparation of a formamidinesulfonic acid by the oxidation of a thiourea with hydrogen peroxide in the presence of a molybdenum catalyst.
The disclosures of these, and all other documents cited in the specification of this application, are incorporated herein by reference.